ICV INJECTION OF THE SEROTONIN 5-HT1B AGONIST CP-93,129 INCREASES THESECRETION OF ACTH, PROLACTIN, AND RENIN AND INCREASES BLOOD-PRESSURE BY NONSEROTONERGIC MECHANISMS

This study tested whether a new serotonin (5-HT1B) agonist, rahydro-4- pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP-93,129), could be used to study the potential role of 5-HT1B receptors in the secretion of adre nocorticotropic hormone (ACTH), prolactin, and renin. CP-93,129 has a high affinity for 5-HT1B receptors but low affinity for other 5-HT rec eptor subtypes. In addition, CP-93,129 does not readily cross the bloo d-brain barrier. The secretion of ACTH, prolactin, and renin is known to be increased after activation of 5-HT receptors. ICV injections of CP-93,129 (100 mu g/kg) increased the plasma concentrations of ACTH, p rolactin, and renin. CP-93,129 also increased blood pressure and reduc ed heart rate. To determine whether these effects of CP-93,129 are cen trally mediated, we compared them with IF injection of the same dose o f CP-93,129. IF-injected CP-93,129 did not alter blood pressure or hea rt rate and did not elevate plasma prolactin and renin concentrations. To determine whether 5-HT1B receptors mediate the central effects of CP-93,129, rats were pretreated with the 5-HT antagonists l-propranolo l or metergoline prior to ICV injections of doses of CP-93,129 (0-100 mu g/kg). The 5-HT1A/1B/2A/2C antagonist metergoline (0.5 mg/kg, IF) f ailed to inhibit the CP-93,129-induced elevation of ACTH, prolactin, o r renin concentrations. In contrast, the 5-HT1A/1B/beta antagonist l-p ropranolol (20 mu g/kg, ICV) inhibited the renin but not the ACTH or p rolactin responses to ICV CP-93,129. However, the same dose of l-propr anolol injected intraarterially (IA) also inhibited the effect of ICV- injected CP-93,129 on renin concentrations and potentiated the CP-93,1 29-induced reduction of heart rate, suggesting that this inhibition is mediated by peripheral beta rather than central 5-HT1B receptors. In conclusion, although CP-93,129 increases the secretion of ACTH, prolac tin, and renin by CNS mechanisms, the data suggest that these effects are mediated by activation of nonserotonin receptors.